. Studies on the total synthesis and evaluation of antitumor antibiotics including (1) fendleridine, (2) lycorine, (3) pancratistatin, (4) (-)-vindoline, (5) an extensive library of ningalin derivatives as multidrug resistant (MDR) reversal drugs, (6) bleomycin derivatives, (7) indolocarbazoles including rebeccamycin, (8) cordytropolone, and (9) sultriecin and key structural analogues are detailed. In the course of the studies, the investigation, development, and implementation of: (1) heteroaromatic azadiene Diels- Alder reactions, (2) the LUMOdiene-controlled Diels-Alder reactions of N-sulfonyl-1- azadienes, (3) the thermal reactions of cyclopropenone ketals including those of reversibly generated p-delocalized singlet vinylcarbenes, and (4) tandem Diels- Alder/1,3-dipolar cycloadditions of 1,3,4-oxadiazoles will be pursued and provide the opportunity to comprehensively extend past studies. The proposed studies include the examination of antitumor compounds that mediate their cellular effects through selective target protein (e.g. PP2A, Pgp) or sequence selective DNA binding and provide well-defined problems on the design, preparation, and evaluation of synthetic, mechanism based analogues in which fundamental studies of the structural features responsible for protein or DNA binding affinity, selectivity, and functional reactivity may be addressed.

Public Health Relevance

New insights into new classes of drugs for the treatment of cancer and methods for their preparation will emerge from the proposed studies.